Further delineation of a rare recessive encephalomyopathy linked to mutations in GFER thanks to data sharing of whole exome sequencing data.

BACKGROUND: Alterations in GFER gene have been associated with progressive mitochondrial myopathy, congenital cataracts, hearing loss, developmental delay, lactic acidosis and respiratory chain deficiency in 3 siblings born to consanguineous Moroccan parents by homozygosity mapping and candidate gene approach (OMIM#613076). Next generation sequencing recently confirmed this association by the finding of compound heterozygous variants in 19-year-old girl with a strikingly similar phenotype, but this ultra-rare entity remains however unknown from most of the scientific community. MATERIALS AND METHODS: Whole exome sequencing was performed as part of a "diagnostic odyssey" for suspected mitochondrial condition in 2 patients, presenting congenital cataracts, progressive encephalomyopathy and hypotrophy and detected unreported compound heterozygous variants in GFER. RESULTS: Thanks to an international data sharing, we found 2 additional patients carrying compound heterozygous variants in GFER. Reverse phenotyping confirmed the phenotypical similarities between the 4 patients. Together with the first literature reports, the review of these 8 cases from 4 unrelated families enables us to better describe this apparently homogeneous disorder, with the clinical and biological stigmata of mitochondrial disease. CONCLUSION: This report highlights the clinical utility of whole exome sequencing and reverse phenotyping for the diagnosis of ultra-rare diseases and underlines the importance of a broad data sharing for accurate clinical delineation of previously unrecognized entities.

Whole-exome sequencing points to considerable genetic heterogeneity of cerebral palsy.

Cerebral palsy (CP) is a common, clinically heterogeneous group of disorders affecting movement and posture. Its prevalence has changed little in 50 years and the causes remain largely unknown. The genetic contribution to CP causation has been predicted to be ~2%. We performed whole-exome sequencing of 183 cases with CP including both parents (98 cases) or one parent (67 cases) and 18 singleton cases (no parental DNA). We identified and validated 61 de novo protein-altering variants in 43 out of 98 (44%) case-parent trios. Initial prioritization of variants for causality was by mutation type, whether they were known or predicted to be deleterious and whether they occurred in known disease genes whose clinical spectrum overlaps CP. Further, prioritization used two multidimensional frameworks-the Residual Variation Intolerance Score and the Combined Annotation-dependent Depletion score. Ten de novo mutations in three previously identified disease genes (TUBA1A (n=2), SCN8A (n=1) and KDM5C (n=1)) and in six novel candidate CP genes (AGAP1, JHDM1D, MAST1, NAA35, RFX2 and WIPI2) were predicted to be potentially pathogenic for CP. In addition, we identified four predicted pathogenic, hemizygous variants on chromosome X in two known disease genes, L1CAM and PAK3, and in two novel candidate CP genes, CD99L2 and TENM1. In total, 14% of CP cases, by strict criteria, had a potentially disease-causing gene variant. Half were in novel genes. The genetic heterogeneity highlights the complexity of the genetic contribution to CP. Function and pathway studies are required to establish the causative role of these putative pathogenic CP genes.

Usability Methods for Ensuring Health Information Technology Safety: Evidence-Based Approaches. Contribution of the IMIA Working Group Health Informatics for Patient Safety.

OBJECTIVES: Issues related to lack of system usability and potential safety hazards continue to be reported in the health information technology (HIT) literature. Usability engineering methods are increasingly used to ensure improved system usability and they are also beginning to be applied more widely for ensuring the safety of HIT applications. These methods are being used in the design and implementation of many HIT systems. In this paper we describe evidence-based approaches to applying usability engineering methods. METHODS: A multi-phased approach to ensuring system usability and safety in healthcare is described. Usability inspection methods are first described including the development of evidence-based safety heuristics for HIT. Laboratory-based usability testing is then conducted under artificial conditions to test if a system has any base level usability problems that need to be corrected. Usability problems that are detected are corrected and then a new phase is initiated where the system is tested under more realistic conditions using clinical simulations. This phase may involve testing the system with simulated patients. Finally, an additional phase may be conducted, involving a naturalistic study of system use under real-world clinical conditions. RESULTS: The methods described have been employed in the analysis of the usability and safety of a wide range of HIT applications, including electronic health record systems, decision support systems and consumer health applications. It has been found that at least usability inspection and usability testing should be applied prior to the widespread release of HIT. However, wherever possible, additional layers of testing involving clinical simulations and a naturalistic evaluation will likely detect usability and safety issues that may not otherwise be detected prior to widespread system release. CONCLUSION: The framework presented in the paper can be applied in order to develop more usable and safer HIT, based on multiple layers of evidence.

Indications of a spatial variation of the fine structure constant.

We previously reported Keck telescope observations suggesting a smaller value of the fine structure constant α at high redshift. New Very Large Telescope (VLT) data, probing a different direction in the Universe, shows an inverse evolution; α increases at high redshift. Although the pattern could be due to as yet undetected systematic effects, with the systematics as presently understood the combined data set fits a spatial dipole, significant at the 4.2 σ level, in the direction right ascension 17.5 ± 0.9 h, declination -58 ± 9 deg. The independent VLT and Keck samples give consistent dipole directions and amplitudes, as do high and low redshift samples. A search for systematics, using observations duplicated at both telescopes, reveals none so far which emulate this result.

RIZ1 repression is associated with insulin-like growth factor-1 signaling activation in chronic myeloid leukemia cell lines.

RIZ1 is a histone methyltransferase whose expression and activity are reduced in many cancers. In chronic myelogenous leukemia (CML), blastic transformation is associated with loss of heterozygosity in the region where RIZ1 is located and with decreased RIZ1 expression. Forced RIZ1 expression in model CML blast crisis (BC) cell lines decreases proliferation, increases apoptosis and enhances differentiation. We characterized molecular mechanisms that may contribute to potential CML tumor suppressor properties of RIZ1. Several RIZ1-regulated genes involved in insulin-like growth factor-1 (IGF-1) signaling were identified using cDNA microarrays. RIZ1 was shown to associate with promoter regions of IGF-1 and to increase histone H3 lysine 9 methylation using chromatin immunoprecipitation assays. IGF-1-blocking antibody was used to demonstrate the importance of autocrine IGF-1 signaling in CML-BC cell line viability. Forced RIZ1 expression in CML-BC cell lines decreases IGF-1 receptor activation and activation of downstream signaling components extracellular signal-regulated kinase 1/2 and AKT. These results highlight the therapeutic potential of inhibiting IGF-1 pathway in the acute phase of CML.

Improving information management in family practice: testing an adult learning model.

Information management training has been neglected in family practice in the UK in the past. An adult learning model for such training is introduced. A pilot study using the adult learning approach showed improvements in information management processes over the six-month study period. The research project described in this paper compares the effectiveness of on-site training using adult learning methods, written information, and no intervention, in 33 family practices in the UK. Nine of the eleven practices in the on-site training group completed the training sessions and eight provided full data, whereas only one of the eleven practices in the written information group, and only one of the eleven practices in the control group provided full data. Preliminary analysis demonstrates that on-site training practices made considerable changes to the information systems in their practices, and appreciated the importance of high-quality data, both for patient care and reporting requirements. Full comparisons of data quality and information management methods are presented, and an assessment of priority training needs for maximum benefit is made.

Interventions for improving information management in family practice.

Information management training has been neglected in family practice in the UK in the past. An adult learning model for such training is introduced. A pilot study using the adult learning approach showed improvements in information management processes over the six-month study period. The research project described in this paper compares the effectiveness of on-site training using adult learning methods, written information, and no intervention, in 33 family practices in the UK. Nine of the eleven practices in the on-site training group completed the training sessions and provided data, whereas only four of the eleven practices in the written information group provided data, and only three of the eleven practices in the control group did so. Preliminary analysis demonstrates that on-site training practices made considerable changes to the information systems in their practices, and appreciated the importance of high-quality data, both for patient care and reporting requirements. Full comparisons of data quality and information management methods are presented, and an assessment of priority training needs for maximum benefit is made.

Taking the problem oriented medical record forward.

The problem oriented medical record (POMR) has proved to be very successful in providing a structure that helps doctors record their notes about patients, and view those notes subsequently in a manner that quickly gives them a good understanding of that patients history. This approach has been validated by the American Institute of Medicine. With the increased use of computer systems that implement the POMR by doctors, the limitations of this structure have become apparent, and there is clearly scope for developing the model further to improve the quality of the data recorded, and adding meaning to it. This paper describes some of the limitations of the POMR, and discusses a number of areas in which it may be extended. Crucially, this is done in a manner which is both implementable, and usable. The extensions explored include some types of entity including encounters, episodes and subproblems; and an alternative view-the Timeline. The terminology used for the extensions is clarified. Mechanisms by which these extensions have been implemented are described. Ways in which systems can manage these extensions automatically are suggested. Such implementations are constrained by the need not to allow the demands of the computer to intrude into the patient encounter. They are also constrained by the requirements for reporting by professional and governmental institutions, and by what is pragmatically feasible in software and hardware.